Feline immunodeficiency virus (FIV) is a neurotropic lentivirus homologous to human immunodeficiency virus type-1 (HIV-1) with similar cellular targets, disease progression and clinical outcome. Growing evidence supports the presence of neurological disease accompanying FIV infection indicating that FIV may provide a useful animal model for AIDS dementia (HIV-1- associated cognitive-motor complex). Current models of HIV- related neurotoxicity suggest that excitotoxic mechanisms may be the final common pathway for neurodegeneration. We hypothesize that similar mechanisms of neurodegeneration will be seen in cats infected with FIV. If similar mechanisms are found, the cat would provide a versatile and convenient animal model inn which both in vitro and in vivo studies could be combined in the same species for analysis of CNS infectivity and neurotoxicity and the development of neuroprotective therapeutic strategies. We propose to develop an in vitro CNS model for the analysis of FIV neurotropism neurotoxicity. To accomplish this, we will establish primary cultures of embryonic (E40-E58) feline neural tissue including neurons, astrocytes and microglia. Virus infection and replication in these cultures will be assessed by inoculating cultures with FIV and evaluating proviral content by PCR-Southern blot analysis. The cellular target(s) of FIV will be determined by evaluating infectivity of purified cultures of astrocytes and microglia as well as by immunohistochemistry or in situ hybridization analyses in mixed cultures. Conditioned medium from various combinations of purified and co-cultured cells inoculated with FIV will be tested on mixed neuronal cultures to evaluate the secretion of toxic factors as well as the role of cell-cell interactions in the production of the toxic substances. To compare the FIV model to HIV, a strong focus will be placed on the role of excitatory amino acid and VIP receptors, calcium channels and cytokines will be used to characterize the pharmacology of the neurotoxicity. Results from the in vitro studies will be correlated with in vivo receptor studies (membrane binding, autoradiography) and neuropathology of late-stage FIV infected cats to relate the in vitro mechanisms of neurotoxicity to patterns of neurodegenerative changes in feline AIDS. Together, we believe these studies will establish FIV infections in cats as a valuable animal model for the investigation of the neurodegenerative changes associated with AIDS dementia in humans.